Synergistic effects of NOD1 or NOD2 and TLR4 activation on mouse sickness behavior in relation to immune and brain activity markers

Abstract

Toll-like receptors (TLRs) and nuclear-binding domain (NOD)-like receptors (NLRs) are sensors of bacterial cell wall components to trigger an immune response. The TLR4 agonist lipopolysaccharide (LPS) is a strong immune activator leading to sickness and depressed mood. NOD agonists are less active but can prime immune cells to augment LPS-induced cytokine production. Since the impact of NOD and TLR co-activation in vivo has been little studied, the effects of the NOD1 agonist FK565 and the NOD2 agonist muramyl dipeptide (MDP), alone and in combination with LPS, on immune activation, brain function and sickness behavior were investigated in male C57BL/6N mice.Intraperitoneal injection of FK565 (0.001 or 0.003 mg/kg) or MDP (1 or 3 mg/kg) 4 h before LPS (0.1 or 0.83 mg/kg) significantly aggravated and prolonged the LPS-evoked sickness behavior as deduced from a decrease in locomotion, exploration, food intake and temperature. When given alone, FK565 and MDP had only minor effects. The exacerbation of sickness behavior induced by FK565 or MDP in combination with LPS was paralleled by enhanced plasma protein and cerebral mRNA levels of proinflammatory cytokines (IFN-γ, IL-1β, IL-6, TNF-α) as well as enhanced plasma levels of kynurenine. Immunohistochemical visualization of c-Fos in the brain revealed that NOD2 synergism with TLR4 resulted in increased activation of cerebral nuclei relevant to sickness.These data show that NOD1 or NOD2 synergizes with TLR4 in exacerbating the immune, sickness and brain responses to peripheral immune stimulation.Our findings demonstrate that the known interactions of NLRs and TLRs at the immune cell level extend to interactions affecting brain function and behavior.

Nod-like receptors are critical for gut-brain axis signaling

“…Highlighting this novel role, mice deficient in Nod1/2 subjected to WAS had pronounced cognitive dysfunction, as well as anxiety-like and depressive-like behaviors, compared to WT(+WAS) controls. These findings complement previous studies by Farzi et al , who showed a role for NLR in regulating sickness behaviors (47). In contrast to these previous findings, however, exposure to an acute stressor was necessary to uncover behavioral deficits in NodDKO mice, suggesting a different mechanism of action is involved in the response to immune stimulation.…”

The GPR55 antagonist CID16020046 protects against intestinal inflammation

“…An open field test with healthy C57BL/6N mice was carried out as previously described. 31 The experimental procedures were approved by the Austrian Federal Ministry of Science, Research and Economy (BMWF-66.010/0037-II/3b/2013). Briefly, mice received 20 mg/kg CID16020046 (or DMSO as vehicle) daily over a period of 6 days.…”

Cellular localization and regulation of receptors and enzymes of the endocannabinoid system in intestinal and systemic inflammation

“…C57BL/6 mice were treated with an intraperitoneal injection of 0.83 mg/kg LPS (Farzi et al 2015) (Sigma, Vienna, Austria) or with PBS alone (vehicle) and killed 4 h later.…”